Abstract
Nature's oligomeric macromolecules have been a long-standing source of inspiration for chemists producing foldamers. Natural systems are frequently conformationally stabilised by macrocyclisation, yet this approach has been rarely adopted in the field of foldamer chemistry. Here we present a new class of chiral cyclic trimers and tetramers formed by macrocyclisation of open-chain foldamer precursors. Symmetrical products are obtained via a [2 + 2] self-assembly approach, while full sequence control is demonstrated through linear synthesis and cyclisation of an unsymmetrical trimer. Structural characterisation is achieved through a combined X-ray and DFT approach, which indicates the tetramers adopt a near-planar conformation, while the trimers adopt a shallow bowl-like shape. Finally, a proof-of-concept experiment is conducted to demonstrate the macrocycles' capacity for cation binding.
Highlights
Nature frequently exploits macrocycles as functional molecules within living systems,[1,2,3] and many of these and their derivatives have been exploited as therapeutics.[4,5,6] Some of the most important drugs for human health are naturally-occurring macrocycles, including vancomycin and cyclosporin
Symmetrical products are obtained via a [2 + 2] self-assembly approach, while full sequence control is demonstrated through linear synthesis and cyclisation of an unsymmetrical trimer
We have previously described a foldamer architecture where dipolar repulsion between adjacent pyrimidine and imidazolidin-2-one components leads to structures with a turn per monomer of $86.15 The attempted synthesis of related pyridine-linked macrocycles by Meth-Cohn failed entirely, generating only oligomeric material,[42] but we hypothesised that the dipole-mediated pre-organisation in our putative linear precursor could favour macrocyclisation over oligomerisation
Summary
Nature frequently exploits macrocycles as functional molecules within living systems,[1,2,3] and many of these and their derivatives have been exploited as therapeutics.[4,5,6] Some of the most important drugs for human health are naturally-occurring macrocycles, including vancomycin and cyclosporin. We present a new class of chiral cyclic trimers and tetramers formed by macrocyclisation of open-chain foldamer precursors.
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